Small heat shock proteins are defined as having molecular weights between 12 and 43 kDa, distinguishing them in size from large heat shock proteins. There are ten human small heat shock proteins: HSPB1-HSPB10. They share common structural characteristics, including a highly conserved 90 amino acid long HSP20 domain and the capacity to form large dynamic oligomers. sHSPs also have the shared function of being intracellular molecular chaperones. As chaperone proteins, sHSPs bind misfolded proteins and prevent them from aggregating. However, they are unable to actively re-fold the protein themselves due to their lack of ATPase activity. Instead, sHSPs sequester the misfolded proteins within the cell to prevent aggregation until a large heat shock protein can assist in refolding.
Although sHSPs share both common structural and functional characteristics, they differ in tissue distribution and expression patterns. HSPB1, HSPB5, HSPB6, HSPB7, and HSPB8 are ubiquitously expressed, and are therefore constitutively present in the brain at low levels. HSPB4 is expressed solely in the lens of the eye, composing nearly 50% of the protein mass in the human lens. HSPB2 and HSPB3 are expressed in muscle and heart and may be selectively expressed in the brain. HSPB9 and HSPB10 are strictly expressed in the testes. HSPB1, HSPB5, and HSPB8 are induced in response to challenges such as heat, glucocorticoids, prostaglandins, and interferon-gamma.
Naturally occurring mutations in conserved regions in several human sHSPs have led to functional consequences including myopathies, cataracts, and Charcot Marie Tooth disease. The crystal structures for several sHSPs have been identified and greater insight has been made into the importance of sHSPs in the regulation of intracellular proteins. However, mounting evidence over the past two decades suggests that sHSPs may not only play a role in maintaining a healthy body, but that they also have protective functions in disease or injury to the central nervous system (CNS).
An upregulation of small heat shock proteins has been seen in many neurodegenerative and neuroinflammatory diseases in both human and rodent brain tissue. sHSPs are upregulated in most protein aggregation diseases of the CNS, and are upregulated in certain neurological diseases that lack classical protein aggregation such as multiple sclerosis and stroke.
Initial reports focusing on one of the small heat shock proteins, alpha B crystallin (HSPB5), suggested that this molecule might be a pathogenic autoantigen, but subsequent studies demonstrated that HSPB5 can be protective in neurological diseases with an inflammatory component. Exogenous administration of cryab can ameliorate the primary mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), making it a therapeutic to treat MS.
A further elucidation of the role of the HSPB family in inflammation and disease is of great interest.
Fragments of small heat shock proteins are described, inter alia, by Ghosh et al., US20080227700A1, US20080280824A1 and US20070185028A1; Ghosh et al. (2005) Biochemistry 44:14854-14869, “Interactive Domains for Chaperone Activity in the Small Heat Shock Protein, Human αB Crystallin”; Ghosh et al. (2006) Cell Stress Chaperones 11:187-197, “The function of the β3 interactive domain in the small heat shock protein and molecular chaperone, human αB crystallin”; Bhattacharyya et al. (2006) Biochemistry 45:3069-3076, “Mini-αB-Crystallin: A Functional Element of αB-Crystallin with Chaperone-like Activity”; Wieske et al. (2001) Eur. J. Biochem. 268:2083-2090, “Defined sequence segments of the small heat shock proteins HSP25 and αB-crystallin inhibit actin polymerization”; Santhoshkumar et al. (2006) Protein Science 15:2488-2498, “Conserved F84 and P86 residues in αB-crystallin are essential to effectively prevent the aggregation of substrate proteins”
Large heat shock proteins are discussed, for example, in Anderton et al. EP751957B1, “Peptide Fragments Of Microbial Stress Proteins and Pharmaceutical Composition Made Thereof for the Treatment And Prevention of Inflammatory Diseases”; Henning et al. US20080161258A1, “Hsp and Supraventricular Arrhythmia”; Gelf and et al. US20070179087A1, “Method for Treating Inflammatory Diseases using Heat Shock Proteins”; Dillmann et al. US20040132190A1, “Gene Therapy for Myocardial Ischemia”.
References of interest also include Sanbe A et al. (2007) JOURNAL OF BIOLOGICAL CHEMISTRY 82:555-563, “Interruption of CryAB-Amyloid Oligomer Formation by HSP22”; Ye et al. (2011) Med Hypotheses 76:296-298, “Locally synthesized HSP27 in hepatocytes: Is it possibly a novel strategy against human liver ischemia/reperfusion injury?”; Lee et al. (2009) J Control Release 137:196-202, “Controlled delivery of heat shock protein using an injectable microsphere/hydrogel combination system for the treatment of myocardial infarction”; Badin et al. (2009) J Cereb Blood Flow Metab 29:254-263, “Protective effect of post-ischaemic viral delivery of heat shock proteins in vivo”; An et al. (2008) FEBS J. 275:1296-1308, “Transduced human PEP-1-heat shock protein 27 efficiently protects against brain ischemic insult”; Kwon et al. (2007) Biochem Biophys Res Commun 363:399-404, “Protective effect of heat shock protein 27 using protein transduction domain-mediated delivery on ischemia/reperfusion heart injury”; Brundel et al. (2006) Circ Res 99:1394-402 “Induction of heat shock response protects the heart against atrial fibrillation”; Badin et al. (2006) J Cereb Blood Flow Metab 26:371-381, “Neuroprotective effects of virally delivered HSPs in experimental stroke”; Martin et al. (1997) CIRCULATION 96:4343-4348, “Small heat shock proteins and protection against ischemic injury in cardiac myocytes”; Islamovic E et al. (2007) J Mol Cell Cardiol 42:862-869 “Importance of small heat shock protein 20 (hsp20) C-terminal extension in cardioprotection”; Sharma et al. (2000) J Biol Chem 275:3767-3771, “Synthesis and Characterization of a Peptide Identified as a Functional Element in αA-crystallin”; and Ghosh et al. (2008) The International Journal of Biochemistry & Cell Biology 40:954-967, “Interactive sequences in the molecular chaperone, human αB crystallin modulate the fibrillation of amyloidogenic proteins”;